Conversion of nitrogen dioxide (no2) to nitric oxide (no)

ABSTRACT

A nitric oxide delivery system, which includes a gas bottle having nitrogen dioxide in air, converts nitrogen dioxide to nitric oxide and employs a surface-active material, such as silica gel, coated with an aqueous solution of antioxidant, such as ascorbic acid. A nitric oxide delivery system may be used to generate therapeutic gas including nitric oxide for use in delivering the therapeutic gas to a mammal.

CLAIM OF PRIORITY

This application claims the benefit of prior U.S. ProvisionalApplication No. 61/098,974, filed on Sep. 22, 2008, which isincorporated by reference in its entirety.

TECHNICAL FIELD

This description relates to controlled generation of nitric oxide.

BACKGROUND

Nitric oxide (NO), also known as nitrosyl radical, is a free radicalthat is an important signaling molecule in pulmonary vessels. Nitricoxide (NO) can moderate pulmonary hypertension caused by elevation ofthe pulmonary arterial pressure. Inhaling low concentrations of nitricoxide (NO), for example, in the range of 20-100 ppm can rapidly andsafely decrease pulmonary hypertension in a mammal by vasodilation ofpulmonary vessels.

Some disorders or physiological conditions can be mediated by inhalationof nitric oxide (NO). The use of low concentrations of inhaled nitricoxide (NO) can prevent, reverse, or limit the progression of disorderswhich can include, but are not limited to, acute pulmonaryvasoconstriction, traumatic injury, aspiration or inhalation injury, fatembolism in the lung, acidosis, inflammation of the lung, adultrespiratory distress syndrome, acute pulmonary edema, acute mountainsickness, post cardiac surgery acute pulmonary hypertension, persistentpulmonary hypertension of a newborn, perinatal aspiration syndrome,haline membrane disease, acute pulmonary thromboembolism,heparin-protamine reactions, sepsis, asthma and status asthmaticus orhypoxia. Nitric oxide (NO) can also be used to treat chronic pulmonaryhypertension, bronchopulmonary dysplasia, chronic pulmonarythromboembolism and idiopathic or primary pulmonary hypertension orchronic hypoxia. Typically, the NO gas is supplied in a bottled gaseousform diluted in nitrogen gas (N₂). Great care has to be taken to preventthe presence of even trace amounts of oxygen (O₂) in the tank of NO gasbecause the NO, in the presence of O₂, is oxidized to nitrogen dioxide(NO₂). Unlike NO, the part per million levels of NO₂ gas is highly toxicif inhaled and can form nitric and nitrous acid in the lungs.

SUMMARY

In one aspect, a system for generating a therapeutic gas includingnitric oxide for use in delivering the therapeutic gas to a mammalincludes a pressure regulator configured to be connected to a gas bottlehaving nitrogen dioxide and capable of providing diffusing gaseousnitrogen dioxide into an air flow wherein the air flow is configured tobe between 5 to 60 liters per minute and a receptacle configured toattach to the pressure regulator. The receptacle includes an inlet, anoutlet, and a surface-active material coated with an aqueous solution ofan antioxidant. The inlet is configured to receive the air flow andfluidly communicate the flow to the outlet through the surface-activematerial to convert the gaseous nitrogen dioxide to nitric oxide atambient temperature.

The air flow can be at 5 liters per minute. The receptacle can have apressure drop of between 0.001 and 0.01 psi. Alternatively, the air flowcan be at 60 liters per minute or lower. The receptacle can have apressure drop of between 0.001 and 0.05 psi. The receptacle can includea cartridge. The surface-active material can be saturated with theaqueous solution of the antioxidant. The surface-active material caninclude a substrate that retains water. The surface-active material caninclude a silica gel. The antioxidant can include ascorbic acid. Theantioxidant can include alpha tocopherol or gamma tocopherol.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWING

FIG. 1 is a block diagram of a cartridge that converts NO₂ to NO.

FIGS. 2-10 are block diagrams of NO delivery systems using the cartridgeof FIG. 1.

FIG. 11 is a diagram of another cartridge that converts NO₂ to NO.

FIGS. 12-14 are diagrams of NO delivery systems using the cartridge ofFIG. 11.

FIG. 15 is a block diagram of a NOx instrument calibration system usingthe cartridge of FIG. 1.

FIG. 16 is a diagram showing placement of the GENO cartridge on the lowpressure side of the pressure regulator.

FIG. 17 is a diagram showing a cartridge that is an integral part of agas bottle cover.

FIG. 18 is a diagram showing a regulator connected to both the outlet ofthe gas bottle and the inlet of the cartridge.

FIGS. 19-21B are diagrams showing aspects of a three-part cartridgedesign.

FIGS. 22A-22B are diagrams showing implementations of a recuperator.

FIG. 23 is a diagram of an NO delivery system using a GeNO cartridgewith a specially designed fitting.

FIG. 24 is a diagram of a diffusion cell connected to a permeation tube.

FIG. 25 is a diagram of a permeation tube with a movable, sliding,non-permeable sheath.

FIG. 26 is a diagram of a common diffusion chamber connected todiffusion tubes, and permeation tubes.

DETAILED DESCRIPTION

When delivering nitric oxide (NO) for therapeutic use to a mammal, itcan be important to avoid delivery of nitrogen dioxide (NO₂) to themammal. Nitrogen dioxide (NO₂) can be formed by the oxidation of nitricoxide (NO) with oxygen (O₂). The rate of formation of nitrogen dioxide(NO₂) is proportional to the oxygen (O₂) concentration multiplied by thesquare of the nitric oxide (NO) concentration—that is,(O₂)*(NO)*(NO)=NO₂

A NO delivery system that converts nitrogen dioxide (NO₂) to nitricoxide (NO) is provided. The system employs a surface-active materialcoated with an aqueous solution of antioxidant as a simple and effectivemechanism for making the conversion. More particularly, NO₂ can beconverted to NO by passing the dilute gaseous NO₂ over a surface-activematerial coated with an aqueous solution of antioxidant. When theaqueous antioxidant is ascorbic acid (that is, vitamin C), the reactionis quantitative at ambient temperatures. The techniques employed by thesystem should be contrasted for other techniques for converting NO₂ toNO. Two such techniques are to heat a gas flow containing NO₂ to over650 degrees Celsius over stainless steel, or 450 degrees Celsius overMolybdenum. Both of these two techniques are used in air pollutioninstruments that convert NO₂ in air to NO, and then measure the NOconcentration by chemiluminescence. Another method that has beendescribed is to use silver as a catalyst at temperatures of 160 degreesCelsius to over 300 degrees Celsius.

One example of a surface-active material is silica gel. Another exampleof a surface-active material that could be used is cotton. Thesurface-active material may be or may include a substrate capable ofretaining water. Another type of surface-active material that has alarge surface area that is capable of absorbing moisture also may beused.

FIG. 1 illustrates a cartridge 100 for generating NO by converting NO₂to NO. The cartridge 100, which may be referred to as a NO generationcartridge, a GENO cartridge, or a GENO cylinder, includes an inlet 105and an outlet 110. Screen and glass wool 115 are located at both theinlet 105 and the outlet 110, and the remainder of the cartridge 100 isfilled with a surface-active material 120 that is soaked with asaturated solution of antioxidant in water to coat the surface-activematerial. The screen and glass wool 115 also is soaked with thesaturated solution of antioxidant in water before being inserted intothe cartridge 100. In the example of FIG. 1, the antioxidant is ascorbicacid.

In a general process for converting NO₂ to NO, an air flow having NO₂ isreceived through the inlet 105 and the air flow is fluidly communicatedto the outlet 110 through the surface-active material 120 coated withthe aqueous antioxidant. As long as the surface-active material remainsmoist and the antioxidant has not been used up in the conversion, thegeneral process is effective at converting NO₂ to NO at ambienttemperature.

The inlet 105 may receive the air flow having NO₂ from an air pump thatfluidly communicates an air flow over a permeation tube containingliquid NO₂, such as in the system 200 of FIG. 2. The inlet 105 also mayreceive the air flow having NO₂, for example, from a pressurized bottleof NO₂, which also may be referred to as a tank of NO₂. The inlet 105also may receive an air flow with NO₂ in nitrogen (N₂), air, or oxygen(O₂). The conversion occurs over a wide concentration range. Experimentshave been carried out at concentrations in air of from about 2 ppm NO₂to 100 ppm NO₂, and even to over 1000 ppm NO₂. In one example, acartridge that was approximately 6 inches long and had a diameter of1.5-inches was packed with silica gel that had first been soaked in asaturated aqueous solution of ascorbic acid. The moist silica gel wasprepared using ascorbic acid (i.e., vitamin C) designated as A.C.Sreagent grade 99.1% pure from Aldrich Chemical Company and silica gelfrom Fischer Scientific International, Inc., designated as SS8 32-1, 40of Grade of 35 to 70 sized mesh. Other sizes of silica gel also areeffective. For example, silica gel having an eighth-inch diameter alsowould work.

The silica gel was moistened with a saturated solution of ascorbic acidthat had been prepared by mixing 35% by weight ascorbic acid in water,stirring, and straining the water/ascorbic acid mixture through thesilica gel, followed by draining. It has been found that the conversionof NO₂ to NO proceeds well when the silica gel coated with ascorbic acidis moist. The conversion of NO₂ to NO does not proceed well in anaqueous solution of ascorbic acid alone.

The cartridge filled with the wet silica gel/ascorbic acid was able toconvert 1000 ppm of NO₂ in air to NO at a flow rate of 150 ml perminute, quantitatively, non-stop for over 12 days. A wide variety offlow rates and NO₂ concentrations have been successfully tested, rangingfrom only a few ml per minute to flow rates of up to 5,000 ml perminute. The reaction also proceeds using other common antioxidants, suchas variants of vitamin E (e.g., alpha tocopherol and gamma tocopherol).

The antioxidant/surface-active material GENO cartridge may be used forinhalation therapy. In one such example, the GENO cartridge may be usedas a NO₂ scrubber for NO inhalation therapy that delivers NO from apressurized bottle source. The GENO cartridge may be used to remove anyNO₂ that chemically forms during inhalation therapy. This GENO cartridgemay be used to help ensure that no harmful levels of NO₂ areinadvertently inhaled by the patient.

First, the GENO cartridge may be used to supplement or replace some orall of the safety devices used during inhalation therapy in conventionalNO inhalation therapy. For example, one type of safety device warns ofthe presence of NO₂ in air when the concentration of NO₂ exceeds apreset or predetermined limit, usually 1 part per million or greater ofNO₂. Such a safety device may be unnecessary when a GENO cartridge ispositioned in a NO delivery system just prior to the patient breathingthe NO laden air. The GENO cartridge converts any NO₂ to NO just priorto the patient breathing the NO laden air, making a device to warn ofthe presence of NO₂ in air unnecessary.

Furthermore, a GENO cartridge placed near the exit of inhalationequipment and gas plumbing lines (which also may be referred to astubing) also reduces or eliminates problems associated with formation ofNO₂ that occur due to transit times in the ventilation equipment. Assuch, use of the GENO cartridge reduces or eliminates the need to ensurethe rapid transit of the gas through the gas plumbing lines that isneeded in conventional applications. Also, a GENO cartridge allows theNO gas to be used with gas balloons to control the total gas flow to thepatient.

Alternatively or additionally, a NO₂ removal cartridge can be insertedjust before the attachment of the delivery system to the patient tofurther enhance safety and help ensure that all traces of the toxic NO₂have been removed. The NO₂ removal cartridge may be a GENO cartridgeused to remove any trace amounts of NO₂. Alternatively, the NO₂ removalcartridge may include heat-activated alumina. A cartridge withheat-activated alumina, such as supplied by Fisher ScientificInternational, Inc., designated as A505-212, of 8-14 sized mesh iseffective at removing low levels of NO₂ from an air or oxygen stream,and yet lets NO gas pass through without loss. Activated alumina, andother high surface area materials like it, can be used to scrub NO₂ froma NO inhalation line.

In another example, the GENO cartridge may be used to generate NO fortherapeutic gas delivery. Because of the effectiveness of the NOgeneration cartridge in converting toxic NO₂ to NO at ambienttemperatures, liquid NO₂ can be used as the source of the NO. Whenliquid NO₂ is used as a source for generation of NO, there is no needfor a pressurized gas bottle to provide NO gas to the delivery system.An example of such a delivery system is described in more detail withrespect to FIG. 2. By eliminating the need for a pressurized gas bottleto provide NO, the delivery system may be simplified as compared with aconventional apparatus that is used to deliver NO gas to a patient froma pressurized gas bottle of NO gas. A NO delivery system that does notuse pressurized gas bottles may be more portable than conventionalsystems that rely on pressurized gas bottles.

FIGS. 2-14 illustrate techniques using silica gel as the surface-activematerial employed in a GENO cartridge. As discussed previously, silicagel is only one example of a surface-active material that may be used ina NO generation system or cartridge.

FIG. 2 illustrates a NO generation system 200 that converts liquid NO₂to NO gas, which then may be delivered to a patient for NO inhalationtherapy. In general, a flow of air generated by an air pump 205 ispassed through a gas permeation cell 235 having liquid NO₂ and its dimerN₂O₄ (collectively, 236). The air flow exiting the gas permeation cell235 includes gaseous NO₂, which is converted to NO gas by a NOgeneration cartridge 240. The NO gas mixture may be delivered to apatient for inhalation therapy, for example, using a mask, a cannula, ora ventilator. The concentration of NO in the NO gas mixture delivered tothe patient may be controlled by controlling the temperature of the gaspermeation cell 235 or the air flow rate through the flow meter 220.

More particularly, the system 200 includes an air pump 205, a regulator210, a flow diverter 215 and a flow meter 220. The system is configuredsuch that air flow 207 from the air pump 205 is divided into a firstflow 225 of 150 ml/min and a second flow 230 of 3000 ml/min. The airflow 207 may be dry or moist.

The flow 225 is passed through a gas permeation cell 235 containingliquid NO₂ and its dimer N₂O₄ (collectively, 236) and a gas permeationtube 237. The permeation cell 235 also may be referred to as apermeation generator, a permeation device or a permeation tube holder.The NO₂ diffuses through the gas porous membrane of the gas permeationcell 235 into the flow 225. In one example, the flow 225 of 150 ml/minof air is allowed to flow through the permeation tube 237, such as apermeation tube supplied by KinTek Corporation of Austin, Tex. Thepermeation tube 237 is designed to release NO₂ at a steady rate suchthat the gas stream leaving the permeation tube in the flow 225 containsabout 840 ppm of NO₂ when the permeation tube 237 is at a temperature of40 degrees Celsius. The region 238 is temperature controlled to maintaina temperature of approximately 40 degrees Celsius. As discussed morefully below, maintaining the temperature of the permeation cell 235helps to control the concentration of NO delivered to the patient.

The 150 ml of air containing 840 ppm of NO₂ then flows through a NOgeneration cartridge 240. In this example, the NO generation cartridge240 is 6 inches long with a diameter of 1.5 inches and contains moistascorbic acid on silica gel, which serves as the conversion reagent. TheNO generation cartridge 240 may be an implementation of cartridge 100 ofFIG. 1. The air stream 225 exiting from the NO generation cartridge 240contains 840 ppm of NO, with all or essentially all of the NO₂ havingbeen converted to NO.

The 225 flow of 150 ml/min with 840 ppm NO then mixes with the flow 230of 3000 ml/min of air or oxygen to produce a flow 247 of 3150 ml/mincontaining 40 ppm of NO. After mixing, the flow 247 passes through asecond NO generation cartridge 245 to remove any NO₂ that may have beenformed during the dilution of NO when the flows 225 and 230 were mixed.The NO generation cartridges 240 and 245 may be sized the same, thoughthis need not necessarily be so. For example, the NO generationcartridge 245 may be sized to have a smaller NO₂ conversion capacitythan the NO generation cartridge 240. The resulting flow 250 of airhaving NO is then ready for delivery to the patient. The system 200 maybe designed to produce a steady flow of NO gas for a period as short asa few hours or as long as 14 days or more. In one test, the system 200was shown to deliver a steady flow of 40 ppm NO gas in air, without NO₂,for over 12 days, where the NO and NO₂ concentrations were measured by achemiluminescent gas analyzer.

As an alternative to the system 200, a NO generation system may includea permeation tube that has a larger flow capacity than the permeationtube 237. In such a case, the larger permeation tube may be able toprocess all of the inhaled air needed to be delivered to the patient sothat, for example, the flow 230 and the conversion tube 245 are notnecessary.

The system 200 can be made portable, for example, if the air pump 205used to supply the air is a portable air pump, such as a simple oil freepump. If oxygen-enriched air is needed by the patient, oxygen can besupplied in addition to, or in lieu of, the air supplied by the air pump205. Oxygen can be supplied, for example, from an oxygen tank or acommercially available oxygen generator. Oxygen also can be suppliedfrom a tank that has NO₂ mixed with O₂.

In some implementations, the permeation cell 238 and/or the twoconversion cartridges 240 and 245 may be disposable items.

The concentration of NO in the flow 250 exiting the system 200 isindependent of the flow 225 through the permeation cell 235, as long asthe flow 225 is greater than a few milliliters per minute. Theconcentration of NO in the flow 250 is a function of the temperature ofthe permeation cell 235 and to a lesser degree the air flow rate 230.For example, with a constant air flow rate 230, the system 200 isdesigned to deliver 40 ppm NO at a temperature of 40 degrees Celsius;however, the concentration of NO can be reduced to 20 ppm NO at 30degrees Celsius and increased to 80 ppm NO at 50 degrees Celsius. Assuch, a temperature controller can be used to adjust the concentrationof the NO gas to be delivered. Once the desired NO concentration isselected and the temperature controller is set to maintain theparticular temperature to deliver the desired concentration, thedelivery rate of NO gas at the desired concentration remains constant.One example of a temperature controller is an oven, such as an ovenavailable from KinTek Corporation, in which the permeation tube isplaced. Another example of a temperature controller is a beaker ofde-ionized water placed on a hot plate where the permeation tube isplaced in the beaker. A thermometer may also be placed in the beaker tomonitor the temperature of the water.

The NO generation system can be used to deliver a steady flow of NO gasmixture for use with a cannula, with the excess gas being vented to theenvironment. The NO generation system can be used with a ventilator,and, in such a case, the delivery from the NO generator must remainsteady and cannot be shut off without endangering the patient receivingthe NO. To handle the increased flow necessary during the air intake tothe patient, the NO gas mixture may be used to inflate and then deflatea flexible bag. If the air flow to the patient is delayed in any way, aNO generation cartridge can be inserted in the NO generation system atthe point immediately prior to inhalation to remove any NO₂ that mayform from NO reacting with O₂ during such a delay. This helps to ensurethat even very small amounts of NO₂ that may be formed in the bag duringthe delay are removed prior to the therapeutic gas flow being inhaled bythe patient.

A detector can be included in the therapeutic gas delivery system 200 todetect the concentration of NO in the therapeutic gas stream. Thedetector can also detect the concentration of NO₂ in the therapeuticgas, if necessary, and may provide a warning if the NO concentration isoutside a predetermined range or if the concentration of NO₂ is above athreshold value. Examples of monitoring techniques includechemiluminescence and electrochemical techniques. The presence of nitricoxide can be detected by, for example, a chemiluminescence detector.

FIG. 3 depicts a NO generation system 300 that converts liquid NO₂ to NOgas, which then may be delivered to a patient for NO inhalation therapy.In contrast to the NO generation system 200 of FIG. 2, the NO generationsystem 300 includes an activated alumina cartridge 345. The activatedalumina cartridge 345 removes any NO₂ that forms during a delay. Incontrast to the NO generation cartridge 240, which removes the NO₂ byconverting the NO₂ to NO, and thereby quantitatively recovering the NO₂,the activated alumina cartridge 345 removes NO₂ from the process gasstream without generating NO.

FIG. 4 illustrates a therapeutic gas delivery system 400 that uses a NOgeneration cartridge 440, which may be an implementation of NOgeneration cartridge 100 of FIG. 1. The system 400 uses a NO source 410to provide gaseous NO in a flow 420 through tubing. In one example, theNO source 410 may be a pressurized bottle of NO. A flow of air 430through the tubing is generated by an air pump 435 and is mixed with theflow 420. The air flow entering the NO generation cartridge 440 includesgaseous NO. Any NO₂ gas that may have formed in flow 420 is removed bythe NO generation cartridge 440. The air flow 450 exiting the NOgeneration cartridge 440 includes therapeutic NO gas but is devoid oftoxic levels of NO₂. The air flow 450 then may be delivered to a patientfor NO inhalation therapy.

FIG. 5 illustrates a therapeutic gas delivery system 500 that uses a NOgeneration cartridge 540, which may be an implementation of NOgeneration cartridge 100 of FIG. 1. In contrast to therapeutic gasdelivery system 400 of FIG. 4, the system 500 generates NO from a NO₂source 510. The NO₂ source 510 may use diffuse liquid NO₂ in an air flow515 generated by an air pump 520 such that the flow 525 exiting the NO₂source 510 includes gaseous NO₂. In some implementations, NO₂ source 510may be a pressurized bottle of NO₂.

In any case, the air flow 525 entering the NO generation cartridge 440includes gaseous NO₂. The NO generation cartridge 440 converts the NO₂gas in flow 525 to NO. The air flow 550 exiting the NO generationcartridge 540 includes therapeutic NO gas but is devoid or essentiallydevoid of NO₂. The air flow 550 then may be delivered to a patient forNO inhalation therapy.

FIG. 6 illustrates a GENO pressure tank system 600 for deliveringtherapeutic gas. The system 600 includes a tank 620 having 40 ppm NO₂ inair, which is commercially available, and a flow controller 622. In oneexample of tank 620, a 300 cu. ft. tank lasts 1.2 days at an air flow of5 L/min.

An air flow 625 a of NO₂ in air exits the flow controller 622 and entersa GENO cartridge 640. The GENO cartridge 640 uses the NO₂ as a precursorand converts the NO₂ to NO. The air flow 625 b exiting the GENOcartridge 640 includes therapeutic NO gas. The air flow 625 b enters anactivated alumina cartridge 660 to remove any NO₂ in the air flow 625 b.The air flow 625 c that exits the activated alumina cartridge 660 isdelivered to a patient for NO inhalation therapy.

The system 600 includes a NOx sample valve 665 and a NO—NO₂ sensor 670operable to detect NO₂. A NO—NO₂ sensor also may be referred to as aNO—NO₂ detector. The NOx sample valve 665 is operable to provide airsamples from air flows 667 a and 667 b to the NO—NO₂ sensor 670. Usingthe NO—NO₂ detector 670 to detect the presence of any NO₂ in air flow667 a may provide an indication of a failure of the GENO cartridge 640,and, as such, provides a prudent safeguard to ensure that no toxic NO₂is delivered to the patient.

In some implementations, the activated alumina cartridge 660 may bereplaced with a GENO cartridge.

In some implementations, the GENO cartridge is attached to the output ofa pressurized gas bottle that has special threads such that the outputfrom the gas bottle can only be interfaced to a GENO cartridge. Forexample, the gas bottle may be filled with breathable oxygen gascontaining NO₂ at a concentration of about 10 to 100 ppm. Such a systemmay use the pressure of the gas bottle to drive the therapeutic gas tothe patient and may have no moving parts, electronics or pumps.Alternatively, the gas bottle may be filled with air that includes NO₂.The use of air or oxygen gas in the pressurized gas bottle may offeradvantages over a conventional method of providing NO in inert nitrogengas, which also necessitated the mixing and instrumentation needed tosafely dilute the concentrated NO gas to a therapeutic dose.

FIG. 7 illustrates a GENO high-concentration NO₂ pressure system 700 fordelivering therapeutic gas. In contrast to the system 600 of FIG. 6, thesystem 700 includes two GENO cartridges 740 and 750 and a switchingvalve 745 to control which of the GENO cartridges 740 or 750 is used.When a NO—NO₂ detector 770 detects the presence of NO₂ in the air flow725 d exiting the GENO cartridge being used, the switching valve 745 canbe manipulated to switch the air flow 725 c to pass through the otherGENO cartridge 740 or 750. The ability to switch to a second GENOcartridge in the event of failure of a first GENO cartridge provides anadditional layer of safety for the patient to whom the therapeutic gasis being delivered.

More particularly, the system 700 includes a tank 720 having 1000 ppmNO₂ in air and a flow controller 722. In the example, the tank 720 is a150 cu. ft. tank at 2250 psi and provides an air flow of 125 cc/min. Atan air flow of 5 L/min of 40 ppm delivered to the patient, the tank 720lasts approximately 23 days. The tank 720 is able to provide an air flowfor a longer period than the expected life of each GENO cartridge 740and 750, which is, in the cartridge used in this example, less than twoweeks. As such, the ability to switch from one GENO cartridge to anotherGENO cartridge helps to ensure that the contents of the tank are used orsubstantially used.

An air flow 725 a of NO₂ in air exits the flow controller 722 and ismixed with an air flow 725 b of 5 L/min that is generated by an airsource 730, such as an air pump. The resulting air flow 725 c enters theswitching valve 745. The switching valve 745 controls which of the GENOcartridges 740 or 750 receives the air flow 725 c. As shown, theswitching valve 745 is set such that the air flow 725 c is provided tothe GENO cartridge 750. The GENO cartridge 750 converts the NO₂ in theair flow 725 c to NO. The air flow 725 d exiting the GENO cartridge 725d includes therapeutic NO gas. The air flow 725 d enters an activatedalumina cartridge 760 to remove any NO₂ in the air flow 725 d. The airflow 725 e that exits the activated alumina cartridge 760 is deliveredto a patient for NO inhalation therapy.

The system 700 includes a NO, sample valve 765 and an NO—NO₂ sensor 770operable to detect NO₂. The NO_(x) sample valve 765 is operable toprovide air samples from air flows 767 a and 767 b to the NO—NO₂ sensor770. Using the NO—NO₂ sensor 770 to detect the presence of any NO₂ inair flow 767 a may provide an indication of a failure of the GENOcartridge being used so that the second GENO cartridge may be used. Insome implementations, the activated alumina cartridge 760 may bereplaced with a GENO cartridge.

FIG. 8 illustrates a GENO high-concentration NO₂ cartridge system 800for delivering therapeutic gas. In contrast to the systems 600 or 700 ofFIGS. 6 and 7, respectively, the system 800 includes ahigh-concentration NO₂ cartridge as the source of the NO₂ used togenerate the NO. More particularly, the system 800 includes an NO₂cartridge 800, such as a small butane tank or a cartridge conventionallyused to deliver CO₂. In one example of the system 800, a NO₂ cartridgewith dimensions of 1 inch by 6 inches and filled with 5% NO₂ in CO₂ wasable to deliver NO₂ for 14 days.

A NO₂ shut-off valve 821 is adjacent to the cartridge 800 to shut-offdelivery of NO₂ from the cartridge 800. The system 800 also includes aflow controller 822 to ensure a generally constant flow rate of the flow825 a exiting the flow controller 822. The flow controller 822 is aglass tube with a small hole through which the gas flow 825 a passes. Invarious implementations of the system 800, the flow controller 822 mayensure a constant flow rate of 1 to 10 cc/min.

The gas flow 825 a having NO₂ exits the flow controller 822 and is mixedwith an air flow 825 b of approximately 5 L/min that is generated by anair source 830. A gas mixer 835 ensures that the air flows 825 a and 825b are fully (or essentially fully) mixed. The resulting air flow 825 cwith NO₂ enters a GENO cartridge 840 that generates NO.

The system 800 also includes an activated alumina cartridge 860 toremove any NO₂ before the therapeutic gas including NO is delivered tothe patient at the rate of approximately 5 L/min. The system 800includes a NO, sample valve 865 and a NO—NO₂ sensor 870 operable todetect NO₂. In some implementations, the activated alumina cartridge 860may be replaced with a GENO cartridge.

FIG. 9 illustrates a GENO permeation system 900 for deliveringtherapeutic gas. The system 900 includes an air flow 925 a ofapproximately 5 L/min that flows into a GENO cartridge 940, which actsto humidify the air. After exiting the GENO cartridge 940, the air flow925 a divides such that an air flow 925 b passes through a permeationdevice 935 and an air flow 925 c does not. The permeation device 935includes permeation tubing 937 and about 10 cc of liquid NO₂ 936 whenthe air flow 925 a begins. The permeation device 935 may be animplementation of the permeation cell 235 of FIG. 2. The permeationdevice 935 is in a permeation oven 939 to maintain a constant, or anessentially constant, temperature to ensure the desired concentration ofNO₂ is diffused into the air flow 925 b. The air flow 925 b and the airflow 925 c mix to form flow 925 d before entering the GENO cartridge950. The GENO cartridge 950 converts the NO₂ to NO.

The system 900 also includes an activated alumina cartridge 960 toreceive air flow 925 e and remove any NO₂ before the therapeutic gasincluding NO is delivered to the patient at the rate of approximately 5L/min. The air flow 925 f that exits the activated alumina cartridge isdelivered to a patient for NO inhalation therapy. The system 900includes a NO, sample valve 965 and a NO—NO₂ sensor 970 operable todetect NO₂.

FIG. 10 illustrates a GENO permeation system 1000 for deliveringtherapeutic gas. In contrast to the system 900 of FIG. 9, the system1000 includes valves 1010 and 1015 to control which of the GENOcartridges 1040 and 1050 first receives the air flow. The system 1000uses liquid NO₂ in a permeation device 1035 as a source of NO₂ to beconverted to NO. The system 1000 also includes an activated aluminacartridge 1060 to remove any NO₂ before the therapeutic gas including NOis delivered to the patient at the rate of approximately 5 L/min. Thesystem 1000 also includes a NOx sample valve 1065 and a NO—NO₂ sensor1070 operable to detect NO₂.

The system 1000 receives an air flow 1025 a of approximately 5 L/mininto the valve 1010, which, together with the valve 1015, controls whichof GENO cartridges 1040 or 1050 the air flow 1025 a first passesthrough. More particularly, by controlling the position of the valves1010 and 1015, the air flow 1025 a can be made to pass through the GENOcartridge 1040, the permeation device 1025, the GENO cartridge 1050, andthen the activated alumina cartridge 1060 before being delivered to thepatient. By manipulating the position of the valves 1010 and 1015, theair flow 1025 a also can be made to pass through the GENO cartridge1050, the permeation device 1025, the GENO cartridge 1040, and then theactivated alumina cartridge 1060 before being delivered to the patient.

For example, when the NO—NO₂ sensor 1070 detects the presence of NO₂ inthe air flow 1025 b, this may signal a need to manipulate the valves1010 and 1015 to cause the order in which the GENO cartridges 1040 and1050 are used to be switched—that is, for example, when the air flow1025 a flows through the GENO cartridge 1040 before flowing through theGENO cartridge 1050, the values 1010 and 1015 are manipulated to causethe air flow 1025 a to flow through GENO cartridge 1050 before flowingthrough the GENO cartridge 1040.

In some commercial applications, NO₂ may be sold at a predeterminedconcentration of approximately 10 to 100 ppm in oxygen or air.

FIG. 11 illustrates a conceptual design of a GENO cartridge 1100 thatconverts NO₂ to NO. The GENO cartridge 1100 may be an implementation ofthe cartridge 100 of FIG. 1. The GENO cartridge 1100 is approximately6-inches long with a 1-inch diameter. The GENO cartridge 1100 includessilica gel saturated with an aqueous solution of ascorbic acid andreceives an air flow from an air or oxygen gas bottle containing NO₂.The air flow through the cartridge 1100 converts NO₂ to NO, which exitsthe cartridge 1100. The GENO cartridge 1100 works effectively atconcentrations of NO₂ from 5 ppm to 5000 ppm. The conversion of NO₂ toNO using the GENO cartridge 1100 does not require a heat source and maybe used at ambient air temperature. The conversion of NO₂ to NO usingthe GENO cartridge 1100 occurs substantially independently of the flowrate of the air flow through the GENO cartridge 1100.

FIG. 12 illustrates a therapeutic gas delivery system 1200 that includesa gas bottle 1220 including NO₂ and an GENO cartridge 1210, which may bean implementation of GENO cartridge 1100 of FIG. 11, for converting NO₂from the gas bottle 1220 to NO for delivery to a patient for NOinhalation therapy. The system 1200 is designed to be portable. In someimplementations, the system 1200 may be designed to operate without theuse of electronics or sensors. Depending on the capacity of the gasbottle 1220, the system 1200 generally has capability to delivertherapeutic NO gas for one to sixteen hours.

The system 1200 may be employed to deliver therapeutic NO gas to apatient on an emergency basis. Examples of such contexts include use byparamedics, military medics or field hospitals, firefighters,ambulances, and emergency rooms or a trauma center of a hospital. Inanother example, a portable therapeutic NO gas delivery apparatus may beused to assist a distressed mountain climber, who may already bebreathing oxygen-enriched air. In yet another example, a portabletherapeutic NO gas delivery apparatus may be used for a patient whoseprimary NO source has failed. In some implementations, a portabletherapeutic NO gas delivery apparatus may be designed for one-time use.

FIG. 13A depicts an exterior view 1300A of a therapeutic gas deliverysystem with a liquid NO₂ source. FIG. 13B illustrates an interior view1300B of the therapeutic gas delivery system shown in FIG. 13A. Thetherapeutic gas delivery system includes a permeation tube 1310 with aliquid NO₂ source, which, for example, may be an implementation of thepermeation device 935 of FIG. 9. The therapeutic gas delivery systemalso includes GENO cartridges 1340 and 1350. The GENO cartridge 1340receives an air flow 1325 a from an air or oxygen source. After exitingthe GENO cartridge 1340, the air flow is divided such that approximately10% of the air flow flows through the permeation tube 1310 by whichgaseous NO₂ is diffused into the air flow. The air flow exiting thepermeation tube 1310 and the other air flow that did not flow throughthe permeation tube 1310 flow through the GENO cartridge 1350, whichconverts the NO₂ to NO. The air flows 1325 b and 1325 c which exit theGENO cartridge 1350 are delivered to the patient for NO inhalationtherapy. The permeation tube 1310 and the GENO cartridges 1340 and 1350may be disposable.

Depending on the capacity of the permeation tube 1310, the therapeuticgas delivery system shown in FIGS. 13A and 13B may have the capabilityto deliver therapeutic NO gas for one to thirty days.

The therapeutic gas delivery system shown in FIGS. 13A and 13B is ableto interface with a ventilator. The therapeutic gas delivery systemshown in FIGS. 13A and 13B also may be employed to deliver therapeuticNO gas to a patient using a canella. For example, delivery of thetherapeutic NO gas may be provided through a canella at a flow of 2liters per minute. The use of the therapeutic gas delivery system with acanella may enable NO therapy to occur outside of a hospital setting.One such example is the use of therapeutic gas delivery system forlong-term NO therapy that takes place at the patient's home.

FIG. 13C depicts the exterior view 1300A of the therapeutic gas deliverysystem shown in FIGS. 13A and 13B relative to a soda can 1350. Asillustrated, the implementation of the therapeutic gas delivery systemshown in FIGS. 13A-13C is a small device relative to conventional NOinhalation therapy systems and is slightly larger than a soda can.

FIG. 14 depicts an exterior view of a therapeutic gas delivery system1400 that uses GENO cartridges to convert NO₂ to NO for use in NOinhalation therapy. The system 1400 includes GENO cartridge ports 1410and 1415 through which a GENO cartridge may be inserted or accessed. Thesystem 1400 includes an inlet port 1420 through which air or oxygenflows into the system 1400 and an associated gauge 1425. The system 1400includes a flow value 1430 and display 1435 for controlling the airflow. The system 1400 includes GENO cartridge flow ports 1440.

The system 1400 also includes a temperature controller 1445 and a NOxdetector 1450, which is accessible through a NOx detector access 1455.The system 1400 also includes a GENO cartridge 1460 that is used toconvert NO₂ to NO essentially just before the air flow having NO exitsthe system 1400 through the outlet 1465. The GENO cartridge 1460 may bereferred to as a safety scrubber. The GENO cartridge 1460 may be smallerthan the GENO cartridges used elsewhere in the system 1400. The system1400 also includes a backup input port 1470 and an exhaust fan 1475.

Additional Example Implementations

These additional example implementations use a gas bottle that containsthe required dose of NO, stored as NO₂, in either oxygen or air or somecombination. The gas is converted on release from the gas bottle asfollows:

Forward 2NO₂→2NO+O₂

This reaction takes place in under a second in the GENO cartridge overAscorbic acid on a moist silica gel matrix. The pressure of the systemshould be held to that needed to force the gas through the system.Typically, the force is about 0.001 to 50 psi, for example, between0.001 and 0.1, or between 0.001 and 0.05 psi. In one embodiment, thepressure of the system can be at 0.005 psi pressure drop aboveatmospheric pressure at low flow rates of the order of 5 liters perminute. In another embodiment, the pressure drop can be 0.04 psi at gasflows as high as 60 liters per minute. In a further embodiment, the GENOcartridge can work well at about 15 to about 25 psi above atmosphericpressure. As soon as the NO is formed, the reverse reaction occurs,namely:

Reverse NO+NO+O₂→2NO₂

The higher the pressure the faster this reaction occurs; indeed its rateis 3^(rd) order in pressure. Converting NO₂ to NO on the high pressureside of the regulator may not occur, when the reverse reaction isoccurring almost as fast as the forward reaction. To address thischallenge, the reverse reaction is minimized by placing the GENOcartridge on the low pressure side of the pressure regulator. This isshown in the FIG. 16 below. Gas exits from the gas bottle, passes thruthe regulator and then flows down the first cartridge, up a connectingtube and then down a second cartridge and then out to the user.

Two cartridges are used serially, one after the other. The reason is tooffer double redundancy. One cartridge works well, but having a secondcartridge provides redundancy. Each cartridge is sized to take theentire contents of the gas bottle with from 40% extra capacity at 100ppm to 20× extra capacity for 20 ppm. As such, this exampleimplementation uses two identical cartridges, which provides double theback up of the using only one cartridge.

Operation and Safety

Another approach to increasing the safety of using the system isshipping the cartridges as an integral part of the gas bottle cover.This is shown in FIG. 17 below together with a regulator:

In such an implementation, the user receives the gas bottle and thenattaches a special regulator to the gas bottle. Using specially keyedCGA fittings, only a GENO regulator could be used. However, the outputof the regulator may be shaped in such a way as to become the inlet portto the GENO cartridge that is attached to the gas bottle cover. Thus,the only way that the user could get gas out of the bottle is to use aregulator with the special CGA fitting, and the only way to get gas outof the regulator would be to connect to the GENO cartridge. In this way,the gas leaving the gas bottle only is able to pass through the GENOcartridges.

This is depicted in FIG. 18. The cartridge remains with the gas bottleat all times. For instance, even when the bottle is returned to berefilled, the used cartridge remains on the gas bottle. The gas fillerthen removes the spent cartridge and replaces the spent cartridge with anew cartridge.

FIG. 18 shows the regulator connected to both the outlet of the gasbottle and the inlet of the cartridge.

For further safety, the output from the cartridge may be keyed as wellso that the NO in oxygen gas can only be used with the special adaptor.

In order to vary the concentration of the NO gas, a different gas bottleis used. One way to help identify the concentration of the NO gas in agas bottle is to have bottles in each concentration have a differentcolor. For example, the bottle with 20 ppm concentration would be blue,whereas the bottle with 100 ppm concentration would be red. Eachconcentration could have its own specially keyed gas bottles, which alsomay help reduce or prevent unintentionally using a concentration of theNO gas that is different than the intended concentration to be used. Inorder to prevent a mix up at the gas bottler, different concentrationsmay be bottled in different factories—for example, bottles with 100 ppmconcentration are bottled at one location, whereas bottles of 20 ppmconcentration are bottled at a different location.

In some implementations, the cartridge design may include only 3 parts.The first part is a twin tube with a third passage between the twintubes, as illustrated in FIG. 19.

FIG. 20 also depicts twin tubes with a third passage between the twintubes.

The end caps of this three-part cartridge design are shown below inFIGS. 21A and 21B.

The interior of the caps is shaped to take the center tube. Sealing thetubes to the caps to the tube may be accomplished with ultrasonicwelding. Sealing the tubes may be accomplished using another technique,such as solvent bonding, O-rings or a clamp seal. A feature of the capsis to mold the male part of the quick disconnect right into the cap;thereby 30 o making the entire cartridge a throw away item.

The cartridge may be assembled as follows:

-   -   1. A plastic flit, with a pore size such that it holds the        powder, is inserted into an end cap.    -   2. The tube and one end cap are welded together, such that the        flit is positioned to act as a filter to prevent powder leaving        the cartridge.    -   3. The tube is filled with the reagent powder. During filling        the powder is compressed and vibrated so as to ensure uniform        and tight packing and the removal of all voids. Once the tube is        filled, the second end cap, with its filter held in place, is        placed over the top of the tube and welded in place.    -   4. If needed, the system is flushed with nitrogen gas to        eliminate oxygen from the system.    -   5. Plastic end caps are placed over the inlet and outlet tubes        so as to prevent the entrainment of moisture.

Recuperator Cartridge

A recuperator cartridge is inserted into the gas plumbing line justprior to inhalation. The purpose of the recuperator is to convert backto NO gas any NO₂ gas that may have been formed in the ventilator andduring storage in a gas bag or other temporary gas storage device. FIGS.22A and 22B illustrate other implementations of a recuperator.

Alternatively, the recuperator may be the same size and form as one ofthe first cartridges. This may further increase the safety of the systemin operation. For example, the recuperator would then provide tripleredundancy to the system with the recuperator being able to convert theentire contents of the gas bottle from NO₂ to NO.

Other Applications

The gas bottle can be used for other applications involving NO. The gasbottle can be used to deliver the bottled gas without the use ofelectronics. The advantages of the system include simplicity, no mixing,no electronics and no software. To operate, the regulator is connectedand the valve opened.

The GENO gas bottle system can also be used with a dilutor. In anexample of implementation, the gas is shipped, for example, as 1000 ppmof NO₂ in oxygen. In a first stage, the user's equipment dilutes thisconcentration down to, perhaps, 20 ppm NO₂. The second stage inserts theGENO cartridge and converts the gas to NO. A recuperator cartridge helpsto reduce the user's concern to about any NO₂ that was formed in the gaslines because the NO₂ would be converted by to NO by the recuperator.Similarly, the recuperator cartridge could be used with existing systemto convert all of the residual NO₂ gas being inhaled into thetherapeutic form, namely NO. The recuperator also ensures that no NO gasis lost from the system and that the patient is receiving the fullprescribed dose.

The fact that GENO can deliver high doses of NO, of the order of 100 to200 ppm or even higher, without the presence of the toxic form, NO₂, maybe important. This addresses the difficulty of a delivered dose beinglimited to around 20 ppm range due to the presence of toxic NO₂, whichlimited the dose that could be achieved. The GENO system eliminates NO₂toxicity problems in the inhaled gas. This may increase, perhaps evengreatly increase, the utility of NO gas for treatment of a multitude ofdiseases, and especially ARDS (“Acute respiratory distress syndrome”).

GENO Cartridge

NO₂/O₂ Gas Bottle Safety

In some implementations of the GeNO technology, NO₂ is dispensed atabout 20 ppm in either oxygen or air and a GeNO cartridge is built ontothe high pressure side of the gas bottle. The cartridge has the capacityto convert the entire NO₂ (which is toxic) contents of the tank to NOgas, which is non toxic (see FIG. 23). This high-pressure cartridge maybe delivered with the tank and designed to be removed only by the tankmanufacturer, due to a specially designed fitting. This cartridge alsomay have a fitting for a regulator with a non-standard connection thatpermits attachment of the GeNO cartridge (low-pressure) which, in turn,has a connection for regular medical usage. This helps to prevent usingthe tank without using the low-pressure cartridge, which is a redundantsafety cartridge that also has the capacity to convert the entirecontents of the NO₂ in the tank. This also helps to reduce thepossibility that someone may attach a non-GeNO regulator on a gas bottlecontaining toxic NO₂ gas in oxygen or air, as well as reducing thepossibility of an accidental release of the tank contents into a room inthe absence of a regulator.

Backup System in Case of Primary Device Failure

Additionally or alternatively, a second, duplicate apparatus (includingtank, regulator and cartridge) is available to permit rapid switching ofthe patient's input source to another tank.

Permeation Tube

Use of Diffusion Cell

A diffusion cell may help to minimize, or even alleviate, the risksassociated with a catastrophic rupture of the permeation tube. Arecommended dose of 20 ppm of NO in 5 liters of air per minute amountsto about 0.33 g of NO₂ per day. A 10 day supply could have 3 to 4 g ofliquid NO₁/N₂O₄. If the permeation tube were to rupture suddenly, thecontents could escape into the room, creating a serious hazard both forthe patent and also for the staff. To help mitigate this safety hazard,the liquid NO₂ may be stored in a strong diffusion cell made ofstainless steel or a strong plastic. The diffusion cell is connected tothe permeation tube by means of a narrow bore hypodermic needle, andacts as the reservoir for the permeation tube. In the event of acatastrophic failure of the permeation tube, the liquid is releasedslowly over hours to days through the narrow bore needle, therebyavoiding a catastrophic and sudden release of toxic NO₂. Furthermore,the diffusion cell can be made strong enough to resist damage from, forexample, crushing, dropping onto concrete, or from sharp objects.

Double Redundancy

In some implementations, the diffusion cell is designed to deliverslightly more NO₂ than needed by the permeation tube. Thus a cell madeof stainless steel with a 4 inch length of hollow tube of 0.002 inch id,would provide enough material to provide slightly more than 20 ppm ofNO₂ in 5 liters of air per minute at 35 degrees Centigrade. Thediffusion rate from the cell should be about 200,000 ng per minute. Ifused in this way, the diffusion cell acts not only as a safety device,but also as a back up control release mechanism for the permeation tube.Even in the event of a catastrophic and sudden failure of the permeationtube, the diffusion cell continues to supply the appropriate dose. Assuch, the diffusion tube is used as a storage device for a permeationtube, and the permeation tube and the diffusion cell work in tandem toprovide double redundancy for safety. (See FIG. 24).

Temperature Effects on Permeation and Diffusion

The permeation rate and/or diffusion rate of NO₂ from the permeationtube and/or the diffusion cell is dependent upon the temperature. In thecase of NO₂, the rate increases by a factor of about 1.9 for every 10°C. increase in temperature. In the typical uses of permeation tubes anddiffusion cells, this rate increase is controlled by controlling thetemperature. For the GENO application, it may be desirable to supply thegas in the temperature range of approximately 15 to 35 degrees C,without controlling the temperature. This may be accomplished, forexample, using the following concepts and techniques.

Permeation Tube.

In a permeation tube, the amount of material that can permeate isdirectly proportional to the length of the tube. Thus, a longer tube candeliver more NO₂ than a shorter one. With this in mind, using a movable,sliding, non-permeable sheath, one is be able to adjust the amount ofpermeation tube that is exposed to regulate the delivery of NO₂ for agiven temperature (see FIG. 25). The length of the tube is scaled toprovide the appropriate dose at the lowest design temperature. For thisexample, the tube is designed to deliver approximately 200,000 ng/min at15 degrees Centigrade. A sleeve is provided which slides over the tubeand covers about ¾ of the length of the tube. Thus, at 15 degreesCentigrade, the entire tube is exposed. If the temperature were 25degrees Centigrade, the rate of diffusion from the tube is doubled, andthis would be compensated for by covering ½ of the active length of thetube. At 35 degrees Centigrade, only ¼ of the tube would be needed tomaintain the same permeation rate of approximately 200,000 ng perminute.

It is contemplated that in a hospital environment where the temperaturesare well controlled, the system would be fitted with a manual slidecalibrated in degrees Centigrade, and the sheath would be set at thetemperature of the room. A thermometer could also be attached to thedevice for added accuracy. A NO₂ cartridge is contemplated that includesa dial that is adjusted for a given temperature in the patient's roomthat slides the sheath on the permeation tube to the appropriateposition, providing the appropriate NO₂ concentration for conversion toNO.

Diffusion Cell.

The rate of release from the diffusion cell is generally proportional tothe length of the narrow bore diffusion needle. In one approach, holesare present in the side of the needle at the ¼, ½, ¾ marks. The threeholes are offset so as to be in the front, the side and the rear of theneedle. An outer sheath with the appropriate slots is fitted around theneedle. By turning the outer sheath, the hole at the mark is uncoveredat 15 degrees Centigrade, whereas all the side holes are covered at 35degrees Centigrade.

In a second approach, the diffusion cell is fitted with four equalnarrow bore needles, with each needle being attached to a shortpermeation tube. Using this approach, the number of tubes is changed,depending upon the temperature.

In these example implementations, the number of tubes mentioned and thenumber of holes are examples only and are not meant to limit theapplication of the contemplated techniques.

NO Weaning-Off Dosage (5 ppm)

As with temperature control, the dosage can also be controlled by usingthe sheath, or varying the number of tubes. A dial on one tube may beattenuated to permit the release of a quarter of the amount of NO₂(assuming full calibration is for a 20 ppm dosage of NO) required toprovide a 5 ppm weaning-off dosage of NO to the patient. Additionally,if four tubes are used in the NO₂ cartridge to provide 20 ppm NO dosage,the dial can cover three of the permeation tubes, leaving the fourthtube to provide the 5 ppm dosage while permitting temperatureadjustments (see FIG. 26). There are various permutations of this, basedupon the discussion provided above.

Rapid Equilibration

One of the challenges in using permeation tubes for medical dosage isthat they can take a long time to come to equilibrium. Because thepermeation tube is always permeating and cannot be switched off, thetube may deliver an initial over dose if the tube was sealed, withoutair flow, into its permeation chamber. It has been observed to take fourhours or more for the tube to reach equilibrium and deliver the correctdose. By covering the active area of the tube with an impermeablesheath, such as a heavy walled Teflon or stainless steel or glass (seeFIG. 25), the permeation of the NO₂ may be blocked during shipping andstorage, and substantially shortens, perhaps greatly shortens, the timeneeded to achieve equilibrium. The sheath can be removed just prior touse and generally 1 hour or less is needed to equilibrate to thecalibrated dosage. By covering the active area of the tube with animpermeable sheath, equilibrium may be reached relatively more quicklywhile helping to prevent an initial over dose that may otherwise occurif the tube was sealed, without air flow, into its permeation chamberwhile not being used for inhalation therapy.

Transport/Rupture Safety

Reinforcement of the diffusion chamber that contains the liquid NO₂,combined with the use of the diffusion cells also helps to prevent theescape of toxic NO₂ in the event of a permeation tube rupture.Additionally, having the sheaths fully lowered, sealing the permeationtubes from the NO₂ cartridge chamber during transportation and storage,and when not in use, helps to provide protection for the tubes. The useof the sheaths also protects the permeation tube when it is used withoutthe diffusion cell.

Transport/Temperature Safety

In some implementations, special heat sensitive ink can be put on theNO₂ cartridge to indicate exposure to overly high temperatures. The inknotifies users not to use the cartridge, since the heat might cause thepermeation tubes to over-pressurize and make them more sensitive torupture. Air-tight seals on the cartridge should help prevent pressuredifferentials between the inside and outside of the permeation tubes.

Example 1

A cartridge six-inches in length with a diameter of 1.5-inches was usedas the NO generation cartridge. Approximately 90 grams 35-70 sized meshsilica gel was soaked in a 25% ascorbic acid solution and air-dried atroom temperature for two hours before being placed in the cartridge. ANO₂ permeation tube was used as the source gas for NO₂. Air from an airpump at a rate of 150 cc/min was flowed into the permeation tube andmixed, after it exited the cartridge, with 3 L/min of ambient air (whichalso was from the air pump). The permeation tube was placed in an ovenwith a temperature set at 32 degrees Celsius to provide a steady streamof 20 ppm NO₂ for the cartridge. The cartridge lasted for 269 hoursbefore ceasing to convert 100% of NO₂ to NO, achieving breakthrough.

Example 2

Two cartridges were each filled using 35-70 sized mesh silica gel andapproximately 40 grams of silica gel. The silica gel was prepared bybeing soaked with a 25% solution of ascorbic acid until completesaturation, and then dried in an oven for one hour at 240 degreesFahrenheit. The ascorbic acid solution was prepared by mixing 25 gramsof ascorbic acid in 100 ml of de-ionized water.

A 1000 ppm NO₂ tank was used to flow NO₂ through the two GENO cartridgesat a rate of 150 cc/min. The two cartridges were placed in series.Ambient air from an air tank was mixed in after the NO₂ had passedthrough the first cartridge and been converted to NO. The air containingNO was then passed through the through the second cartridge in series.The air was passed through the cartridges at a rate of 3 L/min to createa total mixture of 40 ppm NO in air and free of any back reaction ofNO₂.

The two cartridges converted 100% of the NO₂ for 104 hours. At the endof 104 hours, the experiment was stopped because the NO₂ tank was empty.The two cartridges had not yet reached breakthrough after 104 hours.

Results may be improved by drying the silica gel with a gas, such asnitrogen gas, to remove dripping water/ascorbic acid solution from thesilica gel.

Example 3

A plastic PVC cartridge six-inches in length and having a diameter of1.5-inches was used as the NO generator cartridge. The inside of thecartridge was filled with an ascorbic acid-silica mixture. To create theascorbic acid silica mixture, approximately 108 grams of 35-70 sizedmesh was used. The silica gel was soaked in 25% ascorbic acid solutionand then baked in an oven for one hour at 240 degrees Fahrenheit. Theascorbic acid solution was prepared by dissolving 25 grams of ascorbicacid in 100 ml of de-ionized water.

A 1000 ppm NO₂ tank was attached to one end of the cartridge so that1000 ppm of NO₂ flowed through the cartridge at a rate of 150 cc/min.The gas output of the cartridge was then mixed with air using an airpump that flowed at a rate of 3 L/min to create a total mixture of 40ppm NO in air. This cartridge lasted for a total of 122 hours beforeachieving breakthrough.

A NOx detector detected a slight concentration of NO₂, varying from 0.15ppm to 0.25 ppm. The concentration of NO₂ remained steady untilbreakthrough, making it likely that the detected NO₂ concentration wasnot a failure in the 100% efficiency of the cartridge but rather was NO₂that was recreated in tubing after the cartridge. A second, smallercartridge could be placed before the detector to eliminate the small NO₂back reaction.

Example 4

A cartridge was prepared by using 35-70 sized mesh silica gel soaked in25% ascorbic acid solution and air dried for approximately one hour. Apermeation tube was the source for the NO₂ and a KinTek oven was used toraise the level of NO₂ required to 40 ppm. To achieve thisconcentration, the oven was set at 45 degrees Celsius. Air was deliveredto the permeation tube using an air pump at the rate of 200 cc/min.Dilution air was also provided by the air pump at the rate of 3 L/min.To add humidity to the supply of NO₂, two jars filled with water wereattached to the 200 cc/min air before the air entered the permeationtube. This helped to ensure that the air entering the NO₂ source wouldbe moisture rich and therefore that the NO₂ entering the cartridge wouldalso be moisture rich. Approximately every five days, the water in thefirst jar receded to below the end of the tubing and needed to bereplenished so that the water level was above the bottom of the tubeend. The second jar remained untouched for the entire length of theexperiment. The cartridge lasted for 409 hours before ceasing to convert100% of NO₂ to NO, achieving breakthrough.

Example 5

A cartridge six-inches long and having a diameter of 1.5-inches wasprepared by using 108 grams of 35-70 sized mesh silica gel. The silicagel was soaked in a 25% solution of ascorbic acid solution and dried atroom temperature (approximately 70 degrees Fahrenheit) for approximatelytwo hours. The air-dried silica gel was placed inside the cartridge.

A flow of 40 ppm NO₂ was sent through the silica-ascorbic acid cartridgeat a rate of 3.2 L/min. The cartridge lasted for 299 hours beforeceasing to convert 100% of NO₂ to NO, achieving breakthrough. Thecartridge filled with air-dried silica gel lasted longer than acomparable cartridge filled with oven-dried silica gel. Thisdemonstrates oxidation losses due to heating the ascorbic acid in thepresence of air.

Example 6

Approximately 40 grams of 35-70 sized mesh silica gel was soaked in a33% ascorbic acid solution and the dried in an oven at 240 degreesFahrenheit before being placed in the cartridge. Ambient air at a flowrate of 3 L/min though an air pump was mixed with 1000 ppm of NO₂ from atank at a flow rate of 200 cc/min, which created a total flow rate of3.2 L/min and a total NO₂/air mixture of 60 ppm NO₂. The cartridgelasted for 25 hours before losing its 100% conversion ability. Thisdemonstrates that using less silica gel/ascorbic acid in the cartridgeresults in a cartridge that does not last as long.

The use of NO generation cartridge in which NO₂ is quantitativelyconverted to NO is not limited to therapeutic gas delivery and may beapplicable to many fields. For example, the NO generation cartridge maybe included in an air pollution monitor. More particularly, the NOgeneration cartridge can also be used to replace high temperaturecatalytic converters that are widely used today in air pollutioninstrumentation measurement of the airborne concentration of NO₂ gas.The current catalytic converters expend significant electricity, andreplacement of a catalytic convertor with a device that uses a NOgeneration cartridge may simplify the air pollution instruments, andenable lower cost, reduced weight, portable air pollution monitoringinstruments.

In another exemplary use, a NO generation cartridge may be used in a NOxcalibration system. FIG. 15 illustrates an example of a NOx calibrationsystem 1500 that includes a tank 1520 having 1000 ppm NO₂ in air and aflow controller 1522. In the example of FIG. 15, the tank 1520 is animplementation of tank 722 in FIG. 7.

An air flow 1525 a of NO₂ in air exits the flow controller 1522 and ismixed with an air flow 1525 b of 5 L/L/min that is generated by an airsource 1530, such as an air pump. The resulting air flow 1525 c entersthe switching valve 1545. The switching valve 1545 controls whether theGENO cartridge 1540 receives the air flow 1525 c for conversion of theNO₂ in the air flow 1525 c to NO. As shown, the switching valve 1545 isset such that the air flow 1525 c, rather than being provided to theGENO cartridge 1540, is provided to tubing 1550.

The system 1500 includes a NOx instrument 1570 that is to be calibratedto detect NO and NO₂. The NOx instrument 1570 receives the air flow 1525d that includes NO when the air flow 1525 c is directed by switchingvalve 1545 to the GENO cartridge 1540. In contrast, the air flow 1525 dincludes NO₂ when the air flow 1525 c is directed by switching valve1545 to the tubing 1550.

The NOx calibration system 1500 requires a single pressurized tank thatincludes NO₂ to calibrate the NOx instrument 1570 for both NO and NO₂.To do so, for example, the NOx instrument 1570 first may be calibratedfor NO by using the switching valve 1545 to direct the air flow 1525 cthrough the GENO cartridge 1540 (which converts the NO₂ in the air flow1525 c to NO). The NOx instrument 1570 then may be calibrated for NO₂ byusing the switching valve 1545 to direct the air flow 1525 c through thetubing 1550, which results in the air flow 1525 d including NO₂. Inaddition, NOx calibration system 1500 does not require the use of heatto convert NO₂ to NO, for example, to ensure that there is noinadvertent exposure to NO₂ during calibration.

Other implementations are within the scope of the following claims.

What is claimed is:
 1. A system for generating a therapeutic gasincluding nitric oxide for use in delivering the therapeutic gas to amammal comprising: a pressure regulator configured to be connected to agas bottle having nitrogen dioxide and capable of providing diffusinggaseous nitrogen dioxide into an air flow wherein the air flow isconfigured to be between 5 to 60 liters per minute; a receptacleconfigured to attach to the pressure regulator, the receptacle includingan inlet, an outlet, and a surface-active material coated with anaqueous solution of an antioxidant, wherein the inlet is configured toreceive the air flow and fluidly communicate the flow to the outletthrough the surface-active material to convert the gaseous nitrogendioxide to nitric oxide at ambient temperature.
 2. The system of claim1, wherein the air flow is at 5 liters per minute.
 3. The system ofclaim 2, wherein the receptacle has a pressure drop of between 0.001 and0.01 psi.
 4. The system of claim 1, wherein the air flow is at 60 litersper minute or lower.
 5. The system of claim 4, wherein the receptaclehas a pressure drop of between 0.001 and 0.05 psi.
 6. The system ofclaim 1, wherein the receptacle comprises a cartridge.
 7. The system ofclaim 1, wherein the surface-active material is saturated with theaqueous solution of the antioxidant.
 8. The system of claim 1, whereinthe surface-active material comprises a substrate that retains water. 9.The system of claim 1, wherein the surface-active material comprises asilica gel.
 10. The system of claim 1, wherein the antioxidant comprisesascorbic acid.
 11. The system of claim 1, wherein the antioxidantcomprises alpha tocopherol or gamma tocopherol.
 12. A method fordelivering a therapeutic gas including nitric oxide to a mammalcomprising: introducing an air flow into a delivery system, wherein theair flow has a flow rate of between 5 and 60 liters per minute;releasing a gas including nitrogen dioxide from a gas source via apressure regulator; diffusing the gas including nitrogen dioxide intothe air flow, thereby forming an air flow including nitrogen dioxide;introducing the air flow including nitrogen dioxide into a receptacleincluding an inlet, an outlet and an antioxidant; converting thenitrogen dioxide to nitric oxide gas by contacting the nitrogen dioxidewith the antioxidant; and delivering the nitric oxide gas to the mammalin the air flow.
 13. The method of claim 12, wherein the air flow has aflow rate of 5 liters per minute.
 14. The method of claim 12, whereinthe pressure regulator diffuses the gas including nitrogen dioxide intothe air flow.
 15. The method of claim 12, wherein the pressure regulatorincludes a diffusion cell.
 16. The method of claim 15, wherein thediffusion cell is made of stainless steel or plastic.
 17. The method ofclaim 15, wherein the diffusion cell is coupled to at least one needlefrom which the gas including nitrogen dioxide is released.
 18. Themethod of claim 17, wherein each needle is connected to a permeationtube.
 19. The method of claim 12, wherein the pressure regulatorincludes a permeation tube.